title: BET bromodomain inhibition suppresses TH17-mediated pathology.
abstract: Interleukin (IL) 17-producing T helper (T(H)17) cells have been selected through evolution for their ability to control fungal and bacterial infections. It is also firmly established that their aberrant generation and activation results in autoimmune conditions. Using a characterized potent and selective small molecule inhibitor, we show that the bromodomain and extra-terminal domain (BET) family of chromatin adaptors plays fundamental and selective roles in human and murine T(H)17 differentiation from naive CD4(+) T cells, as well as in the activation of previously differentiated T(H)17 cells. We provide evidence that BET controls T(H)17 differentiation in a bromodomain-dependent manner through a mechanism that includes the direct regulation of multiple effector T(H)17-associated cytokines, including IL17, IL21, and GMCSF. We also demonstrate that BET family members Brd2 and Brd4 associate with the Il17 locus in T(H)17 cells, and that this association requires bromodomains. We recapitulate the critical role of BET bromodomains in T(H)17 differentiation in vivo and show that therapeutic dosing of the BET inhibitor is efficacious in mouse models of autoimmunity. Our results identify the BET family of proteins as a fundamental link between chromatin signaling and T(H)17 biology, and support the notion of BET inhibition as a point of therapeutic intervention in autoimmune conditions.
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, MA.
authors.forename: Deanna A
authors.initials: DA
authors.lastname: Mele
authors.forename: Andres
authors.initials: A
authors.lastname: Salmeron
authors.forename: Srimoyee
authors.initials: S
authors.lastname: Ghosh
authors.forename: Hon-Ren
authors.initials: HR
authors.lastname: Huang
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bryant
authors.forename: Jose M
authors.initials: JM
authors.lastname: Lora
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology*; D015551:Autoimmunity / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology*; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D009687:Nuclear Proteins